The repair of wounds in mammalian tissue (e.g., epithelial defects, lesions, or erosions caused by disease, accidental injury, surgical procedure, etc.) involves an orderly, controlled cellular response. Three phases have been described in normal wound healing: acute inflammatory phase, extracellular matrix and collagen synthesis, and remodeling (Wound Repair by Peacock, W. B. Saunders, Philadelphia, Pa., 1984). The sequence of the healing process is initiated during an acute inflammatory phase with the deposition of provisional tissue. This is followed by re-epithelialization, collagen synthesis and deposition, fibroblast proliferation, and neovascularization, all of which ultimately define the remodeling phase (see, for example, Clark, J. Am. Acad. Dermatol. 13:701, 1985). These events are known to be influenced by growth factors and cytokines secreted by inflammatory cells and by epithelial cells, endothelial cells, platelets, and fibroblasts localized at the edges of the wound (see, for example, The Molecular and Cellular Biology of Wound Repair (The Language of Science) Ed. by Clark, Plenum Press, New York, N.Y., 1996; Hunt et al., in The Surgical Wound Ed. by Dineen at al., Lea & Febiger, Philadelphia, Pa., 1981; Nemeth et al., in Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications Ed. by Barbul et al., A. R. Liss, New York, N.Y., 1988; and Assoian et al., Nature 309:804, 1984). During re-epithelialization, cells at the leading edge undergo a phenotypic conversion characterized by a dramatic reorganization of the cytoskeleton, disruption of stable intercellular adhesion, and redistribution of adhesion related molecules. The breakage of the stable intercellular contacts is a prerequisite for initiating re-epithelialization. Following re-epithelialization, reversion to the epithelial phenotype, including the reformation of stable intercellular contacts, must occur if the function of the epithelium is to be fully restored. The failure of epithelial cells to migrate over the wound surface and failure of migrated epithelial cells to remain adherent to the substratum are fundamental causes of debilitating clinical conditions known as persistent epithelial defects (i.e., non healing defects) and recurrent epithelial erosions respectively.
Disorders of wound healing constitute a serious medical problem for several different organ systems including the skin, gastrointestinal tract, and cornea. For example, loss of cell-cell adhesions within the epidermis produces life-threatening blistering skin diseases known as pemphigus foliaceus and pemphigus vulgaris (Cell Adhesion and Human Disease Ed. by Marsh et al., Ciba Foundation Symposium, Vol. 189, John Wiley & Sons, New York, N.Y., 1995). Persistent epithelial defects in the form of delayed re-epithelialization are a characteristic of chronic skin wounds, in particular venous stasis ulcers (Falanga et al., J. Dermatol. Surg. Oncol. 19:764, 1993). Within the cornea, lack of epithelial cell adhesion to the stroma and the basement membrane leads to recurrent corneal erosions (Macaluso et al., in Cornea Ed. by Krachmer, Mosby, St. Louis Mo., 1997). Persistent corneal epithelial defects occur in a wide variety of clinical situations such as in injuries caused by radiation, corneal abrasions or lacerations, chemical burns of the cornea such as alkali and acid burns, keratopathies, keratities and corneal dystrophies. Persistent corneal epithelial defects carry a high risk of corneal perforation and ulceration (Macaluso et al., supra).
Despite the need for more rapid healing of wounds, to date there has been only limited success in accelerating wound healing with pharmaceutical agents. In the case of corneal injuries, the use of epidermal growth factor (Eiferman et al., Invest. Ophthalmol. Vis. Sci. (Suppl.) 28:52, 1987), fibronectin (Nishida et al., J. Cell. Biol. 97:1653, 1983), collagenase inhibitors (Kenyon et al., Invest. Ophthalmol. Vis. Sci. 18:570, 1979), topical steroids (Lass et al., Arch. Ophthalmol. 99:673, 1981), matrix metalloproteinase inhibitors (Murphy et al., Biochemistry 30:8097, 1991), ascorbates (Foster et al., Invest. Ophthalmol. Vis. Sci. (Suppl.) 19:227, 1980), heparin (Aronson, Am. J. Ophthalmol. 70:65, 1970), and tetracyclines (Perry et al., Ophthalmology (Suppl.) 92:77, 1985) does not always result in successful long-term management. For example, topical application to a corneal injury of epidermal growth factor (EGF) (Singh et al., Am. J. Ophthalmol. 103:802, 1987) or fibronectin (Tenn et al., Invest. Ophthalmol. Vis. Sci. (Suppl.) 26:92, 1985), enhances epithelial wound healing but does not prevent recurrent erosion and secondary breakdown of the corneal epithelial surface.
Accordingly, there is a need in the art for additional pharmaceutical agents and compositions that promote the healing of wounds. In particular, there is a need for agents, compositions and therapeutic methods that promote the re-epithelialization of persistent epithelial defects and prevent recurrent epithelial erosions.